Summary: Cells rely on motor proteins such as dynein to move cargo along microscopic highways called microtubules. When these motors or their regulators malfunction, severe neurological disorders can result. New research captured high-resolution, time-resolved “movies” of dynein being activated by its partner protein Lis1, revealing the step-by-step structural changes that unlock and power this essential motor.
Using time-resolved cryo-electron microscopy (cryo-EM), scientists documented 16 distinct three-dimensional conformations during the dynein–Lis1 interaction. These detailed snapshots clarify how Lis1 converts dynein from an autoinhibited state into an active transporter and point to specific sites where future therapies might target dysfunctional dynein or Lis1 in diseases such as lissencephaly.
Key Facts:
- Dynein activation: Lis1 binds sequentially to dynein’s motor domain and then to its microtubule-binding stalk, shifting dynein from an inactive “Phi” conformation to an active “Chi” conformation.
- Imaging advance: Time-resolved cryo-EM captured 16 structural stages of dynein activation, revealing intermediate states not previously observed in still images.
- Clinical relevance: Mapping these conformational steps provides a structural basis for developing drugs that restore dynein function in neurodevelopmental and neurodegenerative disorders linked to Lis1 or dynein mutations.
Source: Salk Institute
Cells use microscopic highways and specialized motor proteins to position organelles, transport RNAs and proteins, and clear cellular debris. Microtubules serve as the tracks and motor proteins like dynein act as the vehicles that carry diverse cargoes to precise locations. Proper motor activity is essential for cell health, and defects can lead to devastating conditions.
Among dynein’s regulatory partners is Lis1. Mutations or dysfunction in Lis1 are associated with lissencephaly, a rare neurodevelopmental disorder characterized by abnormal brain formation. There are currently no cures, and therapeutic development requires a molecular-level understanding of how Lis1 controls dynein.
Researchers at the Salk Institute and UC San Diego used a yeast model system to capture short, high-definition movies of Lis1 activating dynein. Because yeast dynein is functionally conserved with human dynein and yeast cells tolerate altered dynein and Lis1 levels, the team could isolate the proteins, slow their activity by cooling, and record sub-second structural transitions with time-resolved cryo-EM.
Previous structural studies relied on static images taken at different time points, which limited the ability to place each conformation in a continuous activation pathway. The time-resolved approach instead identifies multiple structures over time and compiles them into a dynamic sequence, revealing transitional intermediates and the order in which Lis1 binds and activates dynein.
How Lis1 unlocks dynein
Dynein is a dimer composed of two identical halves. Each half contains: (1) a stalk that binds microtubules, (2) a tail that connects to cargo, and (3) a motor domain that hydrolyzes ATP to power movement. In its inactive state, called “Phi,” dynein adopts a compact, autoinhibited conformation and detaches from microtubules. Activation requires structural rearrangement into an open “Chi” conformation that supports processive motility toward the cell center.
The new cryo-EM movies reveal a sequential two-step mechanism for Lis1-dependent activation. First, one Lis1 half binds the dynein motor domain, relieving autoinhibition and altering the motor’s conformation to increase basal ATP hydrolysis. This conformational change effectively “primes” dynein’s engine for activity. Next, the second Lis1 half engages the dynein stalk, stabilizing the open Chi state and further enhancing motor activity so dynein can efficiently step along microtubules.
Across the dataset, the team solved 16 high-resolution structures that together map intermediate stages between the Phi and Chi states. Several of these conformations were previously unseen and provide a more complete mechanistic model of how Lis1 promotes dynein activation, complex assembly, and motility.
Implications for disease and therapeutics
Understanding the precise contact sites and sequential events through which Lis1 regulates dynein offers clear structural targets for therapeutic design. Future work can test how specific Lis1 or dynein mutations disrupt particular intermediates and contribute to disorders such as lissencephaly. With atomic-level maps of activation intermediates, drug discovery efforts can aim to restore normal conformations or stabilize productive dynein–Lis1 interactions.
As co-corresponding author Agnieszka Kendrick of the Salk Institute notes, the ability to visualize dynein and Lis1 interacting in real time provides a critical foundation for strategies to repair motor dysfunction in both developmental and degenerative neurological conditions.
Additional information
Other authors on the study include Kendrick Nguyen, Eva Karasmanis, Rommie Amaro, Samara Reck-Peterson, and Wen Ma. Funding sources included the American Cancer Society, National Institutes of Health, the Cardiovascular Research Institute of Vermont, Jane Coffin Childs Postdoctoral Fellowship, and the Howard Hughes Medical Institute.
About this genetics and neurodevelopment research news
Author: Salk Comm
Source: Salk Institute
Contact: Salk Comm – Salk Institute
Image: Image credited to Neuroscience News
Original Research (open access): “Multiple steps of dynein activation by Lis1 visualized by cryo-EM” by Agnieszka Kendrick et al., published in Nature Structural & Molecular Biology.
Abstract — Multiple steps of dynein activation by Lis1 visualized by cryo-EM
Cytoplasmic dynein-1 is an essential molecular motor that is regulated in part through autoinhibition. Lis1 is a key regulator linked to the neurodevelopmental disease lissencephaly and has a central role in dynein activation. Using cryo-EM and time-resolved sampling of yeast dynein and Lis1 with ATP, the authors identified conformations representing intermediate states in the activation pathway. Sixteen high-resolution structures were solved, including several distinct dynein and dynein–Lis1 assemblies from the same sample. The data support a model in which Lis1 relieves dynein autoinhibition by increasing basal ATP hydrolysis and promoting conformations compatible with complex assembly and motility, advancing our understanding of dynein activation and Lis1’s contribution to this process.